Mutational analysis of PHEX gene in X-linked hypophosphatemia.
Hypophosphatemic rickets is commonly an X-linked dominant disorder (XLH or HYP) associated with a renal tubular defect in phosphate transport and bone deformities. The XLH gene, referred to as PHEX, or formerly as PEX (phosphate regulating gene with homologies to endopeptidases on the X-chromosome), encodes a 749-amino acid protein that putatively consists of an intracellular, transmembrane, and extracellular domain. PHEX mutations have been observed in XLH patients, and we have undertaken studies to characterize such mutations in 46 unrelated XLH kindreds and 22 unrelated patients with nonfamilial XLH by single stranded conformational polymorphism and DNA sequence analysis. We identified 31 mutations (7 nonsense, 6 deletions, 2 deletional insertions, 1 duplication, 2 insertions, 4 splice site, 8 missense, and 1 within the 5' untranslated region), of which 30 were scattered throughout the putative extracellular domain, together with 6 polymorphisms that had heterozygosity frequencies ranging from less than 1% to 43%. Single stranded conformational polymorphism was found to detect more than 60% of these mutations. Over 20% of the mutations were observed in nonfamilial XLH patients, who represented de novo occurrences of PHEX mutations. The unique point mutation (a-->g) of the 5'untranslated region together with the other mutations indicates that the dominant XLH phenotype is unlikely to be explained by haplo-insufficiency or a dominant negative effect.


Molecularly Imprinted Intelligent Scaffolds for Tissue Engineering Applications.
The development of molecularly imprinted polymers (MIPs) using biocompatible production methods enables the possibility to further exploit this technology for biomedical applications. Tissue engineering (TE) approaches use the knowledge of the wound healing process to design scaffolds capable of modulating cell behavior and promote tissue regeneration. Biomacromolecules bear great interest for TE, together with the established recognition of the extracellular matrix, as an important source of signals to cells, both promoting cell-cell and cell-matrix interactions during the healing process. This review focuses on exploring the potential of protein molecular imprinting to create bioactive scaffolds with molecular recognition for TE applications based on the most recent approaches in the field of molecular imprinting of macromolecules. Considerations regarding essential components of molecular imprinting technology will be addressed for TE purposes. Molecular imprinting of biocompatible hydrogels, namely based on natural polymers, is also reviewed here. Hydrogel scaffolds with molecular memory show great promise for regenerative therapies. The first molecular imprinting studies analyzing cell adhesion report promising results with potential applications for cell culture systems, or biomaterials for implantation with the capability for cell recruitment by selectively adsorbing desired molecules.


Neanderthal and Woolly Mammoth Molecular Resemblance: Genetic Similarities May Underlie Cold Adaptation Suite.
With the ongoing growth of gene-based research in recent decades, examining changes that have taken place in structures over the course of evolution has become increasingly accessible. One intriguing subject at the forefront of evolutionary research is how environmental pressures affect species evolution through epigenetic adaptation. This article presents the available molecular components of adaptation to cold environments in two extinct mammals: the woolly mammoth and the Neanderthal. These two species coexisted in similar geographic and environmental European settings during the Middle and Upper Pleistocene, and both were direct descendants of African ancestors, although both fully evolved and adapted in Europe during the Middle Pleistocene. The authors assessed the degree of resemblance between mammoth and Neanderthal genetic components by reviewing three case studies of relevant gene variants and alleles associated with cold-climate adaptation found in both genomes. Their observations present the likelihood of a molecular resemblance between the suites of cold adaptation traits in the two species.


Proteomics in the chicken: tools for understanding immune responses to avian diseases.
The entire chicken genome sequence will be available by the time this review is in press. Chickens will be the first production animal species to enter the "postgenomic era." This fundamental structural genomics achievement allows, for the first time, complete functional genomics approaches for understanding the molecular basis of chicken normo- and pathophysiology. The functional genomics paradigm, which contrasts with classical functional genetic investigations of one gene (or few) in isolation, is the systematic holistic genetic analyses of biological systems in defined contexts. Context-dependent gene interactions are the fundamental mechanics of all life. Functional genomics uses high-throughput large-scale experimental methods combined with statistical and computational analyses. Projects with expressed sequence tags in chickens have already allowed the creation of cDNA microarrays for large-scale context-dependant mRNA analysis (transcriptomics). However, proteins are the functional units of almost all biological processes, and protein expression very often bears no correlation to mRNA expression. Proteomics, a discipline within functional genomics, is the context-defined analysis of complete complements of proteins. Proteomics bridges the "sequence-to-phenotype gap;" it complements structural and other functional genomics approaches. Proteomics requires high capital investment but has ubiquitous biological applications. Although currently the fastest-growing human biomedical discipline, new paradigms may need to be established for production animal proteomics research. The prospective promise and potential pitfalls of using proteomics approaches to improve poultry pathogen control will be specifically highlighted. The first stage of our recently established proteomics program is global protein profiling to identify differentially expressed proteins in the context of the commercially important pathogens. Our trials and tribulations in establishing our proteomics program, as well some of our initial data to understand chicken immune system function, will be discussed.


Development and Validation of Liquid Chromatographic Method for Estimation of Naringin in Nanoformulation.
A simple, precise, accurate, rapid, and sensitive reverse phase high performance liquid chromatography (RP-HPLC) method with UV detection has been developed and validated for quantification of naringin (NAR) in novel pharmaceutical formulation. NAR is a polyphenolic flavonoid present in most of the citrus plants having variety of pharmacological activities. Method optimization was carried out by considering the various parameters such as effect of pH and column. The analyte was separated by employing a C18 (250.0 × 4.6 mm, 5 μm) column at ambient temperature in isocratic conditions using phosphate buffer pH 3.5: acetonitrile (75 : 25% v/v) as mobile phase pumped at a flow rate of 1.0 mL/min. UV detection was carried out at 282 nm. The developed method was validated according to ICH guidelines Q2(R1). The method was found to be precise and accurate on statistical evaluation with a linearity range of 0.1 to 20.0 μg/mL for NAR. The intra- and interday precision studies showed good reproducibility with coefficients of variation (CV) less than 1.0%. The mean recovery of NAR was found to be 99.33 ± 0.16%. The proposed method was found to be highly accurate, sensitive, and robust. The proposed liquid chromatographic method was successfully employed for the routine analysis of said compound in developed novel nanopharmaceuticals. The presence of excipients did not show any interference on the determination of NAR, indicating method specificity.


Transplantation of human bone marrow mesenchymal stem cells as a thin subretinal layer ameliorates retinal degeneration in a rat model of retinal dystrophy.
Vision incapacitation and blindness associated with retinal degeneration affect millions of people worldwide. Cell based therapy and specifically transplantation of human adult bone marrow-derived stem cells (hBM-MSCs) present possible treatment strategy. Subretinal transplantation of human or rat BM-MSCs was shown previously to improve retinal function in Royal College Surgeons (RCS) rats. In those studies cells were transplanted via a transscleral-transchoroidal approach, creating a localized subretinal bleb. Limited number of cells could be injected and photoreceptor rescue was restricted to areas in proximity to the injection site. Here we describe a new surgical method for subretinal transplantation that facilitates uniform distribution of transplanted cells as a thin layer along most of the subretinal space. We assessed the therapeutic effect of hBM-MSCs on RCS rats when transplanted either subretinally or intravitreally. We also examined whether a second transplantation can prolong the therapeutic effect. A cell suspension of 2.5 × 10(6) cells in 5 μl was injected subretinally or intravitreally in RCS rats at 28 days postnatal. In the subretinal group, hBM-MSCs were transplanted posterior to the limbus in the superotemporal part of the eye through a longitudinal triangular scleral tunnel reaching the choroid. In the intravitreal group, the cells were injected into the superotemporal part of the vitreous cavity. In cross sections of subretinally transplanted eyes, removed 2 h following transplantation, hBM-MSCs were distributed as a near-homogenous thin layer along most of the subretinal space. In some animals the cells were also detected in the choroid. In the intravitreal injection group, hBM-MSCs were clustered in the vitreous cavity. Transplanted cells could be detected up to 2 weeks after transplantation but not at later time points. Retinal function and structure were assessed by electroretinogram (ERG) and histology analysis, respectively. Six weeks post transplantation, the mean maximal scotopic ERG b-wave amplitude response recorded in RCS control eyes was 1.2 μV. By contrast, in transplanted eyes mean responses of 56.4 μV and 66.2 μV were recorded in the intravitreally and subretinally transplanted eyes, respectively. In the subretinal group, retinal function was significantly higher in transplanted compared with control eyes up to 20 weeks following transplantation. By contrast, in the intravitreal group, rescue of retinal function persisted only up to 12 weeks following transplantation. Histological analysis revealed that 8 weeks following subretinal transplantation, the retinas of control eyes were dystrophic, with outer nuclear layer (ONL) containing a single cell layer. An extensive photoreceptor rescue was demonstrated in transplanted eyes at this time point, with 3-4 cell layers in the ONL along the entire retina. A second subretinal transplantation at 70 days postnatal did not enhance or prolong the therapeutic effect of hBM-MSCs. No immunosuppressants were used and long-term safety analysis demonstrated no gross or microscopic adverse effects. Taken together our findings suggest that transplantation of hBM-MSCs as a thin subretinal layer enhances the therapeutic effect and the safety of cell transplantation.


Visualization of the Critical Isthmus by Tracking Delayed Potential in Edited Windows for Scar-Related Ventricular Tachycardia.
Identifying the critical isthmus of slow conduction is crucial for successful treatment of scar-related ventricular tachycardia. Current 3D mapping is not designed for tracking the critical isthmus and may lead to a risk of extensive ablation. We edited the algorithm to track the delayed potential in order to visualize the isthmus and compared the edited map with a conventional map. We marked every point that showed delayed potential with blue color. After substrate mapping, we edited to reset the annotation from true ventricular potential to delayed potential and then changed the window of interest from the conventional zone (early, 50-60%; late, 40-50% from peak of QRS) to the edited zone (early, 80-90%; late, 10-20%) for every blue point. Finally, we compared the propagation maps before and after editing. We analyzed five scar-related ventricular tachycardia cases. In the propagation maps, the resetting map showed the critical isthmus and entrance and exit sites of tachycardia that showed figure 8 reentry. However, conventional maps only showed the earliest ventricular activation sites and searched for focal tachycardia. All of the tachycardia cases were terminated by ablating the area around the isthmus. Identifying the channel and direction of the critical isthmus by a new editing method to track delayed potential is essential in scar-related tachycardia.


Insights into the immuno-molecular biology of Angiostrongylus vasorum through transcriptomics--prospects for new interventions.
Angiostrongylus vasorum is a metastrongyloid nematode of dogs and other canids of major clinical importance in many countries. In order to gain first insights into the molecular biology of this worm, we conducted the first large-scale exploration of its transcriptome, and predicted essential molecules linked to metabolic and biological processes as well as host immune responses. We also predicted and prioritized drug targets and drug candidates. Following Illumina sequencing (RNA-seq), 52.3 million sequence reads representing adult A. vasorum were assembled and annotated. The assembly yielded 20,033 contigs, which encoded proteins with 11,505 homologues in Caenorhabditis elegans, and additional 2252 homologues in various other parasitic helminths for which curated data sets were publicly available. Functional annotation was achieved for 11,752 (58.6%) proteins predicted for A. vasorum, including peptidases (4.5%) and peptidase inhibitors (1.6%), protein kinases (1.7%), G protein-coupled receptors (GPCRs) (1.5%) and phosphatases (1.2%). Contigs encoding excretory/secretory and immuno-modulatory proteins represented some of the most highly transcribed molecules, and encoded enzymes that digest haemoglobin were conserved between A. vasorum and other blood-feeding nematodes. Using an essentiality-based approach, drug targets, including neurotransmitter receptors, an important chemosensory ion channel and cysteine proteinase-3 were predicted in A. vasorum, as were associated small molecular inhibitors/activators. Future transcriptomic analyses of all developmental stages of A. vasorum should facilitate deep explorations of the molecular biology of this important parasitic nematode and support the sequencing of its genome. These advances will provide a foundation for exploring immuno-molecular aspects of angiostrongylosis and have the potential to underpin the discovery of new methods of intervention.


Pushing the Limits on Metal-Organic Frameworks as a Catalyst Support: NU-1000 Supported Tungsten Catalysts for o-Xylene Isomerization and Disproportionation.
Acid-catalyzed skeletal C-C bond isomerizations are important benchmark reactions for the petrochemical industries. Among those, o-xylene isomerization/disproportionation is a probe reaction for strong Brønsted acid catalysis, and it is also sensitive to the local acid site density and pore topology. Here, we report on the use of phosphotungstic acid (PTA) encapsulated within NU-1000, a Zr-based metal-organic framework (MOF), as a catalyst for o-xylene isomerization at 523 K. Extended X-ray absorption fine structure (EXAFS), 31P NMR, N2 physisorption, and X-ray diffraction (XRD) show that the catalyst is structurally stable with time-on-stream and that WO x clusters are necessary for detectable rates, consistent with conventional catalysts for the reaction. PTA and framework stability under these aggressive conditions requires maximal loading of PTA within the NU-1000 framework; materials with lower PTA loading lost structural integrity under the reaction conditions. Initial reaction rates over the NU-1000-supported catalyst were comparable to a control WO x-ZrO2, but the NU-1000 composite material was unusually active toward the transmethylation pathway that requires two adjacent active sites in a confined pore, as created when PTA is confined in NU-1000. This work shows the promise of metal-organic framework topologies in giving access to unique reactivity, even for aggressive reactions such as hydrocarbon isomerization.


Two theories of muscle strength augmentation using percutaneous electrical stimulation.
Electrical stimulation of muscle is a commonly used, well-substantiated strategy that physical therapists use to augment strength in patients with muscle weakness. Two distinctly different theories of strength augmentation using percutaneous muscle stimulation are presented. The first theory proposes that augmentation of muscle strength with electrically elicited muscle contractions occurs in a similar manner to augmentation of muscle strength with voluntary exercise. Electrically elicited muscle contractions of relatively high intensity with low numbers of repetitions strengthen muscle proportionally to the external load on the muscle in a manner that is equivalent to voluntary contraction. The second theory proposes that augmentation of muscle strength using percutaneous stimulation is fundamentally different from augmentation of strength with voluntary exercise. This theory uses the physiological differences between electrically elicited and voluntary contractions, such as the reversal of motor unit recruitment order, as a basis for argument. Both theories are partially substantiated using published literature. Strategies for testing both theories are also presented.


Special phase transformation and crystal growth pathways observed in nanoparticles†.
Phase transformation and crystal growth in nanoparticles may happen via mechanisms distinct from those in bulk materials. We combine experimental studies of as-synthesized and hydrothermally coarsened titania (TiO2) and zinc sulfide (ZnS) with thermodynamic analysis, kinetic modeling and molecular dynamics (MD) simulations. The samples were characterized by transmission electron microscopy, X-ray diffraction, synchrotron X-ray absorption and scattering, and UV-vis spectroscopy. At low temperatures, phase transformation in titania nanoparticles occurs predominantly via interface nucleation at particle-particle contacts. Coarsening and crystal growth of titania nanoparticles can be described using the Smoluchowski equation. Oriented attachment-based crystal growth was common in both hydrothermal solutions and under dry conditions. MD simulations predict large structural perturbations within very fine particles, and are consistent with experimental results showing that ligand binding and change in aggregation state can cause phase transformation without particle coarsening. Such phenomena affect surface reactivity, thus may have important roles in geochemical cycling.


A Transient Translaminar GABAergic Interneuron Circuit Connects Thalamocortical Recipient Layers in Neonatal Somatosensory Cortex.
GABAergic activity is thought to influence developing neocortical sensory circuits. Yet the late postnatal maturation of local layer (L)4 circuits suggests alternate sources of GABAergic control in nascent thalamocortical networks. We show that a population of L5b, somatostatin (SST)-positive interneuron receives early thalamic synaptic input and, using laser-scanning photostimulation, identify an early transient circuit between these cells and L4 spiny stellates (SSNs) that disappears by the end of the L4 critical period. Sensory perturbation disrupts the transition to a local GABAergic circuit, suggesting a link between translaminar and local control of SSNs. Conditional silencing of SST+ interneurons or conversely biasing the circuit toward local inhibition by overexpression of neuregulin-1 type 1 results in an absence of early L5b GABAergic input in mutants and delayed thalamic innervation of SSNs. These data identify a role for L5b SST+ interneurons in the control of SSNs in the early postnatal neocortex.


First molecular determination of herpesvirus from two mysticete species stranded in the Mediterranean Sea.
Herpesvirus can infect a wide range of animal species: mammals, birds, reptiles, fish, amphibians and bivalves. In marine mammals, several alpha- and gammaherpesvirus have been identified in some cetaceans and pinnipeds species. To date, however, this virus has not been detected in any member of the Balaenoptera genus. Herpesvirus was determined by molecular methods in tissue samples from a male fin whale juvenile (Balaenoptera physalus) and a female common minke whale calf (Balaenoptera acutorostrata) stranded on the Mediterranean coast of the Region of Valencia (Spain). Samples of skin and penile mucosa from the fin whale and samples of skin, muscle and central nervous system tissue from the common minke whale tested positive for herpesvirus based on sequences of the DNA polymerase gene. Sequences from fin whale were identical and belonged to the Alphaherpesvirinae subfamily. Only members of the Gammaherpesvirinae subfamily were amplified from the common minke whale, and sequences from the muscle and central nervous system were identical. Sequences in GenBank most closely related to these novel sequences were viruses isolated from other cetacean species, consistent with previous observations that herpesviruses show similar phylogenetic branching as their hosts. To our knowledge, this is the first molecular determination of herpesvirus in the Balaenoptera genus. It shows that herpesvirus should be included in virological evaluation of these animals.


Sex inequalities in access to care for patients with diabetes in primary care: questionnaire survey.
Health experiences differ between men and women. The health services have focused their attention on gynaecological health problems in women, however women with non-gynaecological health problems could be unintentionally neglected. Given the increased prevalence of diabetes, the healthcare needs and experiences of women with diabetes are increasing. To determine the extent of sex inequalities in access to care for diabetes in primary care. Cross-sectional population-based questionnaire study. Twenty-three general practices spread through 23 different primary care trusts in the former Trent Region, UK. The study consisted of a random sample of 1,673 patients with diabetes. Outcomes measured were odds ratios adjusted for age for measures of physical access to the GP's surgery; ease of obtaining appointments; access to primary care professionals; levels of routine diabetes care received; barriers to physical activity, problems eating and psychological distress as measured by the 18 score Diabetes Health Profile. Women were less likely than men to report that they had talked to their GP or practice nurse about their diabetes in the previous 12 months and were less likely to report that they were able to book routine appointments at convenient times. Almost 40% of all patients with diabetes reported difficulty in visiting the GP's surgery for their diabetes care, and women were more likely to report difficulties in visiting the surgery than men. Women were more likely than men to be afraid to go out alone (7.9% versus 3.6%) and more likely to be housebound (6.8% versus 2.4%). Women had significantly higher scores for eating problems and barriers to physical activity than men. Women report more problems with access to diabetes care than men. If the ambitions of the National Service Framework are to be met, then positive action needs to be taken to improve access to care for women with diabetes.


Type 1 insulin-like growth factor receptor translocates to the nucleus of human tumor cells.
The type 1 insulin-like growth factor receptor (IGF-1R) is a transmembrane glycoprotein composed of two extracellular alpha subunits and two beta subunits with tyrosine kinase activity. The IGF-1R is frequently upregulated in cancers and signals from the cell surface to promote proliferation and cell survival. Recent attention has focused on the IGF-1R as a target for cancer treatment. Here, we report that the nuclei of human tumor cells contain IGF-1R, detectable using multiple antibodies to alpha- and beta-subunit domains. Cell-surface IGF-1R translocates to the nucleus following clathrin-mediated endocytosis, regulated by IGF levels. The IGF-1R is unusual among transmembrane receptors that undergo nuclear import, in that both alpha and beta subunits traffic to the nucleus. Nuclear IGF-1R is phosphorylated in response to ligand and undergoes IGF-induced interaction with chromatin, suggesting direct engagement in transcriptional regulation. The IGF dependence of these phenomena indicates a requirement for the receptor kinase, and indeed, IGF-1R nuclear import and chromatin binding can be blocked by a novel IGF-1R kinase inhibitor. Nuclear IGF-1R is detectable in primary renal cancer cells, formalin-fixed tumors, preinvasive lesions in the breast, and nonmalignant tissues characterized by a high proliferation rate. In clear cell renal cancer, nuclear IGF-1R is associated with adverse prognosis. Our findings suggest that IGF-1R nuclear import has biological significance, may contribute directly to IGF-1R function, and may influence the efficacy of IGF-1R inhibitory drugs.


Optic nerve sheath diameter-guided extubation plan in obese patients undergoing robotic pelvic surgery in steep Trendelenburg position: A report of three cases.
Robotic pelvic surgery requires steep Trendelenburg positioning with pneumoperitoneum which causes raised thoracic and intracranial pressures. In obese patients, the basal thoracic pressures are high. Increased intrathoracic pressure can decrease the cranial venous flow leading to deficient intracranial absorption of cerebrospinal fluid and a further increase in intracranial pressure. Operating times are also longer due to unfavorable anatomy. Such patients frequently have a delayed awakening from anaesthesia due to a combination of factors such as hypercapnoea, acidosis, and raised intracranial pressures. Normocapnoea can be achieved in a ventilated patient towards the end of surgery. In cases where the anaesthetic agents have been washed out and normocapnoea has been achieved, the intracranial pressure may be an important factor causing delayed emergence. The sonographically measured optic nerve sheath diameter correlates with the intracranial pressure. We report three cases of robot-assisted pelvic surgery in obese patients where we used the optic nerve sheath diameter as a guide for the timing of extubation.


Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist.
Dopamine modulates movement, cognition, and emotion through activation of dopamine G protein-coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor (D3R) in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. On the intracellular side of the receptor, a locked conformation of the ionic lock and two distinctly different conformations of intracellular loop 2 are observed. Docking of R-22, a D3R-selective antagonist, reveals an extracellular extension of the eticlopride binding site that comprises a second binding pocket for the aryl amide of R-22, which differs between the highly homologous D2R and D3R. This difference provides direction to the design of D3R-selective agents for treating drug abuse and other neuropsychiatric indications.


Interleukin-4 activated macrophages mediate immunity to filarial helminth infection by sustaining CCR3-dependent eosinophilia.
Eosinophils are effectors in immunity to tissue helminths but also induce allergic immunopathology. Mechanisms of eosinophilia in non-mucosal tissues during infection remain unresolved. Here we identify a pivotal function of tissue macrophages (Mϕ) in eosinophil anti-helminth immunity using a BALB/c mouse intra-peritoneal Brugia malayi filarial infection model. Eosinophilia, via C-C motif chemokine receptor (CCR)3, was necessary for immunity as CCR3 and eosinophil impairments rendered mice susceptible to chronic filarial infection. Post-infection, peritoneal Mϕ populations proliferated and became alternatively-activated (AAMϕ). Filarial AAMϕ development required adaptive immunity and interleukin-4 receptor-alpha. Depletion of Mϕ prior to infection suppressed eosinophilia and facilitated worm survival. Add back of filarial AAMϕ in Mϕ-depleted mice recapitulated a vigorous eosinophilia. Transfer of filarial AAMϕ into Severe-Combined Immune Deficient mice mediated immunological resistance in an eosinophil-dependent manner. Exogenous IL-4 delivery recapitulated tissue AAMϕ expansions, sustained eosinophilia and mediated immunological resistance in Mϕ-intact SCID mice. Co-culturing Brugia with filarial AAMϕ and/or filarial-recruited eosinophils confirmed eosinophils as the larvicidal cell type. Our data demonstrates that IL-4/IL-4Rα activated AAMϕ orchestrate eosinophil immunity to filarial tissue helminth infection.


Design of a simple cryogenic system for ultraviolet-visible absorption spectroscopy with a back-reflectance fiber optic probe.
We report a convenient and inexpensive technique for the rapid acquisition of absorption spectra from small samples at cryogenic temperatures using a home built cryostat with novel collection optics. A cylindrical copper block was constructed with a coaxial bore to hold a 4.00 mm diameter electron paramagnetic resonance (EPR) tube and mounted on a copper feed in thermal contact with liquid nitrogen. A 6.35 mm diameter hole was bored into the side of the cylinder so a fiber optic cable bundle could be positioned orthogonally to the EPR tube. The light passing through the sample is reflected off of the opposing surfaces of the EPR tube and surrounding copper, back through the sample. The emergent light is then collected using the fiber optic bundle and analyzed using a dispersive spectrometer. Absorption spectra for KMnO4 were measured between 400 and 700 nm. Absorption intensity at 506, 525, 545, and 567 nm was found to be proportional to concentration, displaying Beer's law-like behavior. The EPR tube had an internal diameter of 3.2 mm; the double pass of the probe beam through the sample affords a central path length of about 6.4 mm. Comparing these measurements with those recorded on a conventional tabletop spectrometer using a cuvette with a 10.00 mm path length, we consistently found a ratio between intensities of 0.58 rather than the anticipated 0.64. These 6% smaller values we attribute to the curvature of the EPR tube and transmission/reflection losses. This system is particularly well-suited to studying the kinetics and dynamics of chemical reactions at cryogenic temperatures. The rapid response (100 ms) and multiplex advantage provided the opportunity of recording simultaneous time courses at several wavelengths following initiation of a chemical reaction with a pulsed laser source.


miRNA-155 silencing reduces sciatic nerve injury in diabetic peripheral neuropathy.
Neuropathic pain represents one of the most common complications associated with diabetes mellitus (DM) that impacts quality of life. Accumulating studies have highlighted the involvement of miRNAs in DM. Thus, the current study aimed to investigate the roles of miR-155 in diabetic peripheral neuropathy (DPN). In vitro DPN models were established using rat Schwann cells (SCs) by treatment with 5.5 mM glucose. Gain- or loss-of-function studies were conducted to determine the effect of miR-155 on Nrf2, cellular function, reactive oxygen species and inflammation. Rat DNP models were established by streptozotocin injection and damage of sciatic nerve. Next, miR-155 antagomir or agomir was employed to investigate the effects associated with miR-155 on motor and sciatic nerve conduction velocity (MNCV, SNCV), angiogenesis and inflammatory response in vivo. Nrf2 was identified to be a target of miR-155 by dual-luciferase reporter gene assay. Silencing of miR-155 or restoration of Nrf2 promoted cell proliferation, inhibited apoptosis and alleviated inflammation in vitro. miR-155 antagomir-induced inhibition increased MNCV and SNCV, strengthened angiogenesis and alleviated inflammation in DPN rats. Additionally, the effects exerted by miR-155 were reversed when Nrf2 was restored both in vitro and in vivo. Taken together, the key findings of our study provide evidence indicating that miR-155 targeted and suppressed Nrf2 in DPN. miR-155 silencing was found to alleviate sciatic nerve injury in DPN, highlighting its potential as a therapeutic target for DPN.


A Link Between Hypoglycemia and Progression of Atherosclerosis in the Veterans Affairs Diabetes Trial (VADT).
To determine whether a link exists between serious hypoglycemia and progression of atherosclerosis in a substudy of the Veterans Affairs Diabetes Trial (VADT) and to examine whether glycemic control during the VADT modified the association between serious hypoglycemia and coronary artery calcium (CAC) progression. Serious hypoglycemia was defined as severe episodes with loss of consciousness or requiring assistance or documented glucose <50 mg/dL. Progression of CAC was determined in 197 participants with baseline and follow-up computed tomography scans. During an average follow-up of 4.5 years between scans, 97 participants reported severe hypoglycemia (n = 23) or glucose <50 mg/dL (n = 74). Serious hypoglycemia occurred more frequently in the intensive therapy group than in the standard treatment group (74% vs. 21%, P < 0.01). Serious hypoglycemia was not associated with progression of CAC in the entire cohort, but the interaction between serious hypoglycemia and treatment was significant (P < 0.01). Participants with serious hypoglycemia in the standard therapy group, but not in the intensive therapy group, had ∼50% greater progression of CAC than those without serious hypoglycemia (median 11.15 vs. 5.4 mm(3), P = 0.02). Adjustment for all baseline differences, including CAC, or time-varying risk factors during the trial, did not change the results. Examining the effect of serious hypoglycemia by on-trial HbA1c levels (cutoff 7.5%) yielded similar results. In addition, a dose-response relationship was found between serious hypoglycemia and CAC progression in the standard therapy group only. Despite a higher frequency of serious hypoglycemia in the intensive therapy group, serious hypoglycemia was associated with progression of CAC in only the standard therapy group.


From Transcriptomics to Treatment in Inherited Optic Neuropathies.
Inherited optic neuropathies, including Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), are monogenetic diseases with a final common pathway of mitochondrial dysfunction leading to retinal ganglion cell (RGC) death and ultimately loss of vision. They are, therefore, excellent models with which to investigate this ubiquitous disease process-implicated in both common polygenetic ocular diseases (e.g., Glaucoma) and late-onset central nervous system neurodegenerative diseases (e.g., Parkinson disease). In recent years, cellular and animal models of LHON and DOA have matured in parallel with techniques (such as RNA-seq) to determine and analyze the transcriptomes of affected cells. This confluence leaves us at a particularly exciting time with the potential for the identification of novel pathogenic players and therapeutic targets. Here, we present a discussion of the importance of inherited optic neuropathies and how transcriptomic techniques can be exploited in the development of novel mutation-independent, neuroprotective therapies.


Lobe-specific mediastinal nodal dissection is sufficient during lobectomy by video-assisted thoracic surgery or thoracotomy for early-stage lung cancer.
Lobectomy with complete mediastinal lymphadenectomy is considered standard for patients with early-stage non-small cell lung cancer (NSCLC). However, the benefits of complete lymphadenectomy are unproven. There is evidence suggesting a predictable pattern of mediastinal nodal drainage. This study analyzed the frequency and pattern of mediastinal nodal disease and its impact on outcome in patients with early-stage NSCLC. Patients with clinical N0/N1 NSCLC staged with CT scans and PET scans were identified. Disease involvement of resected nodal stations was recorded. Patterns of recurrence in patients who underwent lobectomy with complete mediastinal systematic lymph node sampling (SLNS) were compared with those who underwent lobe-specific mediastinal SLNS. From July 2004 to April 2011, 370 patients were identified. Complete SLNS was performed in 282 patients. Fifteen patients (5.3%) in the group with complete SLNS were found to have N2 disease after pathologic evaluation. Patients with left-sided tumors were more likely to have pathologic N2 disease than were patients with right-sided tumors (P = .03). Only one patient (0.36%) had positive N2 disease in the distal mediastinum while skipping lobe-specific mediastinal nodes. In addition, patients with complete SLNS had a rate of recurrence similar to that of the group that had lobe-specific mediastinal evaluation (20.6% vs 18.2%, P = .68). Mediastinal N2 metastases follow predictable lobe-specific patterns in patients with negative preoperative CT scans and PET scans. Lobe-specific N2 nodal evaluation results in a recurrence rate similar to that of complete mediastinal evaluation. Lobe-specific mediastinal nodal evaluation appears acceptable in patients with early-stage NSCLC.


Increasing the power of the Mann-Whitney test in randomized experiments through flexible covariate adjustment.
The Mann-Whitney U test is frequently used to evaluate treatment effects in randomized experiments with skewed outcome distributions or small sample sizes. It may lack power, however, because it ignores the auxiliary baseline covariate information that is routinely collected. Wald and score tests in so-called probabilistic index models generalize the Mann-Whitney U test to enable adjustment for covariates, but these may lack robustness by demanding correct model specification and do not lend themselves to small sample inference. Using semiparametric efficiency theory, we here propose an alternative extension of the Mann-Whitney U test, which increases its power by exploiting covariate information in an objective way and which lends itself to permutation inference. Simulation studies and an application to an HIV clinical trial show that the proposed permutation test attains the nominal Type I error rate and can be drastically more powerful than the classical Mann-Whitney U test.


Comprehensive nutritional status in patients with long-standing Crohn disease currently in remission.
Malnutrition is observed frequently and is an important complication in patients with Crohn disease (CD). The pathophysiology of malnutrition in this disorder is complex. To obtain a comprehensive picture of nutritional status in patients with long-standing CD that was clinically in remission, we assessed four measures of nutritional status in 32 patients (18 women and 14 men) and 32 matched healthy control subjects: 1) body composition, 2) dietary intake, 3) biochemical indexes of nutrition, and 4) and muscle strength (as a functional index). Mean daily intakes of fiber and phosphorus were significantly lower in CD patients than in control subjects. Serum concentrations of several nutrients (beta-carotene, vitamin C, vitamin E, selenium, and zinc) and activity of the enzyme glutathione peroxidase were also significantly lower in CD patients, as were antioxidant status and serum concentrations of magnesium and vitamin D. Percentage body fat and hamstring muscle strength were significantly lower in male CD patients than in control subjects, whereas muscle strength of the quadriceps was preserved. In conclusion, this study showed a variety of nutritional and functional deficiencies in patients with long-standing CD in remission, especially in male patients with a high lifetime prednisone dose. A comprehensive nutritional assessment seems superior to the assessment of a single dimension of nutritional status.


Effects of rigidity on the selectivity of protein kinase inhibitors.
Established strategies for discovering selective kinase inhibitors are target-centric as they often target certain structural or reactive features in the target kinase. In the absence of such prominent features, there is a lack of general methods for discovering selective inhibitors. Here we describe a new strategy that exploits conformational flexibility of kinases for achieving selective kinase inhibition. Through ring closure, we designed and synthesized a panel of isoquinoline-containing compounds as rigidified analogs of an amidophenyl-containing parent compound. These analogs potently inhibit kinases including Abl and BRAF but have diminished inhibition against some other kinases compared to the parent compound. Sequence analysis reveals that many of the kinases that are potently inhibited by the isoquonoline-containing compounds contain a long insertion within their catalytic domains. A crystal structure of one rigid compound bound to BRAF confirmed its binding mode. Our findings highlight the potential of a novel strategy of rigidification for improving the selectivity of kinase inhibitors.


Distinct mechanisms produce functionally complementary actions of neuropeptides that are structurally related but derived from different precursors.
Many bioactive neuropeptides containing RFamide at their C terminus have been described in both invertebrates and vertebrates. To obtain insight into the functional logic of RFamide signaling, we investigate it here in the feeding system of Aplysia. We focus on the expression, localization, and actions of two families of RFamide peptides, the FRFamides and FMRFamide, in the central neuronal circuitry and the peripheral musculature that generate the feeding movements. We describe the cloning of the FRFamide precursor protein and show that the FRFamides and FMRFamide are derived from different precursors. We map the expression of the FRFamide and FMRFamide precursors in the feeding circuitry using in situ hybridization and immunostaining and confirm proteolytic processing of the FRFamide precursor by mass spectrometry. We show that the two precursors are expressed in different populations of sensory neurons in the feeding system. In a representative feeding muscle, we demonstrate the presence of both FRFamides and FMRFamide and their release, probably from the processes of the sensory neurons in the muscle. Both centrally and in the periphery, the FRFamides and FMRFamide act in distinct ways, apparently through distinct mechanisms, and nevertheless, from an overall functional perspective, their actions are complementary. Together, the FRFamides and FMRFamide convert feeding motor programs from ingestive to egestive and depress feeding muscle contractions. We conclude that these structurally related peptides, although derived from different precursors, expressed in different neurons, and acting through different mechanisms, remain related to each other in the functional roles that they play in the system.


An approach to catheter ablation of cavotricuspid isthmus dependent atrial flutter.
Much of our understanding of the mechanisms of macro re-entrant atrial tachycardia comes from study of cavotricuspid isthmus (CTI) dependent atrial flutter. In the majority of cases, the diagnosis can be made from simple analysis of the surface ECG. Endocardial mapping during tachycardia allows confirmation of the macro re-entrant circuit within the right atrium while, at the same time, permitting curative catheter ablation targeting the critical isthmus of tissue located between the tricuspid annulus and the inferior vena cava. The procedure is short, safe and by demonstration of an electrophysiological endpoint - bidirectional conduction block across the CTI - is associated with an excellent outcome following ablation. It is now fair to say that catheter ablation should be considered as a first line therapy for patients with documented CTI-dependent atrial flutter.


pH Gradient Reversal: An Emerging Hallmark of Cancers.
Several tumors exhibit pH gradient reversal, with acidification of extracellular pH (pHe) and alkalinization of intracellular pH (pHi). The pH gradient reversal is evident even during the preliminary stages of tumorigenesis and is crucial for survival and propagation of tumors, irrespective of their pathology, genetics and origins. Moreover, this hallmark seems to be present ubiquitously in all malignant tumors. Based on these facts, we propose a new emerging hallmark of cancer "pH gradient reversal". Normalizing pH gradient reversal through inhibition of various proton transporters such as Na(+)-H(+) exchanger (NHE), Vacuolar-type H(+)-ATPase (V-ATPase), H(+)/K(+)-ATPases and carbonic anhydrases (CAs) has demonstrated substantial therapeutic benefits. Indeed, inhibition of NHE1 is now being regarded as the latest concept in cancer treatment. A recent patent deals with the utilization of cis-Urocanic acid to acidify the pHi and induce apoptosis in tumors. Another patent reports therapeutic benefit by inhibiting Lactate Dehydrogenase - 5 (LDH-5) in various cancers. Several patents have been formulated by designing drugs activated through acidic pHe providing a cancer specific action. The purpose of this review is to analyze the available literature and help design selective therapies that could be a valuable adjunct to the conventional therapies or even replace them.


In vivo 1H MR spectroscopy of human head and neck lymph node metastasis and comparison with oxygen tension measurements.
Current diagnostic methods for head and neck metastasis are limited for monitoring recurrence and assessing oxygenation. 1H MR spectroscopy (1H MRS) provides a noninvasive means of determining the chemical composition of tissue and thus has a unique potential as a method for localizing and characterizing cancer. The purposes of this investigation were to measure 1H spectral intensities of total choline (Cho), creatine (Cr), and lactate (Lac) in vivo in human lymph node metastases of head and neck cancer for comparison with normal muscle tissue and to examine relationships between metabolite signal intensities and tissue oxygenation status. Volume-localized Lac-edited MRS at 1.5 T was performed in vivo on the lymph node metastases of 14 patients whose conditions were untreated and who had primary occurrences of squamous cell carcinoma. MRS measurements were acquired also from the neck muscle tissue of six healthy volunteers and a subset of the patients. Peak areas of Cho, Cr, and Lac were calculated. Tissue oxygenation (pO2) within the abnormal lymph nodes was measured independently using an Eppendorf polarographic oxygen electrode. Cho:Cr ratios were significantly higher in the nodes than in muscle tissue (node Cho:Cr = 2.9 +/- 1.6, muscle Cho:Cr = 0.55 +/- 0.21, P = .0006). Lac was significantly higher in cancer tissue than in muscle (P = .01) and, in the nodes, showed a moderately negative correlation with median pO2 (r = -.76) over a range of approximately 0 to 30 mm Hg. Nodes with oxygenation values less than 10 mm Hg had approximately twice the Lac signal intensity as did nodes with oxygenation values greater than 10 mm Hg (P = .01). Cho signal intensity was not well correlated with pO2 (r = -.46) but seemed to decrease at higher oxygenation levels (>20 mm Hg). 1H MRS may be useful for differentiating metastatic head and neck cancer from normal muscular tissue and may allow for the possibility of assessing oxygenation. Potential clinical applications include the staging and monitoring of treatment.


Measuring the impact of MS on walking ability: the 12-Item MS Walking Scale (MSWS-12).
To develop a patient-based measure of walking ability in MS. Twelve items describing the impact of MS on walking (12-Item MS Walking Scale [MSWS-12]) were generated from 30 patient interviews, expert opinion, and literature review. Preliminary psychometric evaluation (data quality, scaling assumptions, acceptability, reliability, validity) was undertaken in the data generated by 602 people from the MS Society membership database. Further psychometric evaluation (including comprehensive validity assessment, responsiveness, and relative efficiency) was conducted in two hospital-based samples: people with primary progressive MS (PPMS; n = 78) and people with relapses admitted for IV steroid treatment (n = 54). In all samples, missing data were low (< or =3.8%), item test-retest reproducibility was high (> or =0.78), scaling assumptions were satisfied, and reliability was high (> or =0.94). Correlations between the MSWS-12 and other scales were consistent with a priori hypotheses. The MSWS-12 (relative efficiency = 1.0) was more responsive than the Functional Assessment of Multiple Sclerosis mobility scale (0.72), the 36-Item Short Form Health Survey physical functioning scale (0.33), the Expanded Disability Status Scale (0.03), the 25-ft Timed Walk Test (0.44), and Guy's Neurologic Disability Scale lower limb disability item (0.10). The MSWS-12 satisfies standard criteria as a reliable and valid patient-based measure of the impact of MS on walking. In these samples, the MSWS-12 was more responsive than other walking-based scales.


Muscle dysfunction caused by a KATP channel mutation in neonatal diabetes is neuronal in origin.
Gain-of-function mutations in Kir6.2 (KCNJ11), the pore-forming subunit of the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel, cause neonatal diabetes. Many patients also suffer from hypotonia (weak and flaccid muscles) and balance problems. The diabetes arises from suppressed insulin secretion by overactive KATP channels in pancreatic beta-cells, but the source of the motor phenotype is unknown. By using mice carrying a human Kir6.2 mutation (Val59-->Met59) targeted to either muscle or nerve, we show that analogous motor impairments originate in the central nervous system rather than in muscle or peripheral nerves. We also identify locomotor hyperactivity as a feature of KATP channel overactivity. These findings suggest that drugs targeted against neuronal, rather than muscle, KATP channels are needed to treat the motor deficits and that such drugs require high blood-brain barrier permeability.


Hedonic drinking engages a supraspinal inhibition of thermal nociception in adult rats.
The taste of sucrose is commonly used to provide pain relief in newborn humans and is innately analgesic to neonatal rodents. In adulthood, sucrose remains a strong motivator to feed, even in potentially hazardous circumstances (ie, threat of tissue damage). However, the neurobiological mechanisms of this endogenous reward-pain interaction are unclear. We have developed a simple model of sucrose drinking-induced analgesia in Sprague-Dawley rats (6-10 weeks old) and have undertaken a behavioral and pharmacological characterization using the Hargreaves' test of hind-paw thermal sensitivity. Our results reveal an acute, potent, and robust inhibitory effect of sucrose drinking on thermal nociceptive behaviour that unlike the phenomenon in neonates is independent of endogenous opioid signalling and does not seem to operate through classical descending inhibition of the spinal cord circuitry. Experience of sucrose drinking had a conditioning effect whereby the apparent expectancy of sucrose enabled water alone (in euvolemic animals) to elicit a short-lasting placebo-like analgesia. Sweet taste alone, however, was insufficient to elicit analgesia in adult rats intraorally perfused with sucrose. Instead, the sucrose analgesia phenomenon only appeared after conditioning by oral perfusion in chronically cannulated animals. This sucrose analgesia was completely prevented by systemic dosing of the endocannabinoid CB1 receptor antagonist rimonabant. These results indicate the presence of an endogenous supraspinal analgesic circuit that is recruited by the context of rewarding drinking and is dependent on endocannabinoid signalling. We propose that this hedonic sucrose-drinking model may be useful for further investigation of the supraspinal control of pain by appetite and reward.


Altered desaturation and elongation of fatty acids in hormone-sensitive lipase null mice.
Hormone-sensitive lipase (HSL) is expressed predominantly in adipose tissue, where it plays an important role in catecholamine-stimulated hydrolysis of stored lipids, thus mobilizing fatty acids. HSL exhibits broad substrate specificity and besides acylglycerides it hydrolyzes cholesteryl esters, retinyl esters and lipoidal esters. Despite its role in fatty acid mobilization, HSL null mice have been shown to be resistant to diet-induced obesity. The aim of this study was to define lipid profiles in plasma, white adipose tissue (WAT) and liver of HSL null mice, in order to better understand the role of this multifunctional enzyme. This study used global and targeted lipidomics and expression profiling to reveal changed lipid profiles in WAT, liver and plasma as well as altered expression of desaturases and elongases in WAT and liver of HSL null mice on high fat diet. Decreased mRNA levels of stearoyl-CoA desaturase 1 and 2 in WAT were consistent with a lowered ratio of 16:1n7/16:0 and 18:1n9/18:0 in WAT and plasma. In WAT, increased ratio of 18:0/16:0 could be linked to elevated mRNA levels of the Elovl1 elongase. This study illustrates the importance of HSL for normal lipid metabolism in response to a high fat diet. HSL deficiency greatly influences the expression of elongases and desaturases, resulting in altered lipid profiles in WAT, liver and plasma. Finally, altered proportions of palmitoleate, a recently-suggested lipokine, in tissue and plasma of HSL null mice, could be an important factor mediating and contributing to the changed lipid profile, and possibly also to the decreased insulin sensitivity seen in HSL null mice.


Comparison between carbon monoxide poisoning from hookah smoking versus other sources.
Introduction: Carbon monoxide exposure is a relatively unknown risk of smoking hookah. Dozens of cases of hookah-associated carbon monoxide toxicity have been described over the past decades, but smoking hookah is generally perceived as safe. Only recently have larger series of hookah-associated carbon monoxide toxicity been published. This study evaluates the incidence of hookah-associated carbon monoxide toxicity over 4 years, and compares the exposures from hookah against other carbon monoxide sources.Methods: This is a retrospective cohort study of all patients with carbon monoxide toxicity referred for hyperbaric oxygen therapy at an urban hyperbaric oxygen referral center from January 2015 through December 2018. Cases of hookah-associated carbon monoxide toxicity were compared to patients exposed to other carbon monoxide sources, with an analysis of patient comorbidities, symptomatology, and laboratory evaluation.Results: Over a 48-month period, 376 patients underwent hyperbaric oxygen therapy for carbon monoxide exposure. After exclusions, 265 patients with carbon monoxide toxicity from various sources were analyzed. There were 58 patients with hookah-associated carbon monoxide toxicity (22%). The proportion of hookah-associated carbon monoxide cases increased markedly in the latter years: 2015: 9.5%, 2016: 8.6%, 2017: 24.1%, 2018 41.6%. In the final 2 years analyzed, hookah smoking was the most frequent source of carbon monoxide toxicity referred for therapy. Hookah-associated carbon monoxide patients were younger(28.1 vs. 45.0 years, mean difference 16.8 years, 95% confidence interval: 11.5, 22.1 years, p < 0.001) and more likely to be female (60% vs. 46.6%, p = 0.06) than patients exposed to other carbon monoxide sources. The mean difference in carboxyhemoglobin concentration between hookah associated and those exposed to other carbon monoxide sources was 4.6% (mean 20.1% vs. 24.6%, 95%CI: 1.7, 7.5, p = 0.002).Conclusion: A substantial portion of patients with severe carbon monoxide toxicity was exposed through smoking hookah. The incidence of hookah-related carbon monoxide toxicity appears to be increasing.


Travel medicine considerations for North American immigrants visiting friends and relatives.
In the United States, 10% of the population was born outside of its borders. Immigrants and their children frequently return to visit their homeland, referred to as visiting friends and relatives (VFRs). They account for a disproportionately high volume of international travel. Searches of MEDLINE, World Health Organization, Centers for Disease Control and Prevention, International Society of Travel Medicine, and American Society of Tropical Medicine computerized databases, conference proceedings and abstracts, US Census Bureau, bibliographies of pertinent articles, and travel medicine texts. Priority was given to recent (1996-2003) evidence, addressing VFR travelers. General sources including travel medicine and immigrant health were also used. Immigrants visiting friends and relatives experience excessive rates of travel-related morbidity and mortality. Lack of pretravel care is common due to patient and clinician barriers to care, preexisting health beliefs, and incomplete childhood vaccinations. Travel patterns increase risk with VFRs traveling to high-risk destinations. Susceptibility to infectious and noninfectious illnesses is often increased because of multiple preexisting medical problems and extremes of age. Infectious diseases differ in etiology and magnitude from those of traditional travelers. For example with malaria, VFRs are frequently prescribed inappropriate prophylaxis or take none at all, have longer stays, spend time in high-risk areas, and do not appropriately adhere to chemoprophylaxis regimens. Effective pretravel health advice, guidelines, and services for this high-risk population are essential. There are already a number of useful and readily available databases that may aid clinicians in providing optimal travel-related preventive and therapeutic care. Immigrants who are visitors of friends and relatives in other countries account for a high volume of international travelers and are at markedly increased risk of travel-related illness. New strategies are needed to properly address the needs of VFR travelers. Pretravel services should be convenient, accessible, affordable, culturally competent, and if possible, located within clinics serving immigrant populations. Clinicians caring for VFRs should be knowledgeable about their travel-related risks and have access to regularly updated, detailed pretravel health information.


Headache in children: effectiveness of multidisciplinary treatment in a tertiary paediatric headache clinic.
The aim of this article is to evaluate the effectiveness of a specific multidisciplinary treatment programme for children with headache and to describe the concept and settings of the Children's Headache Clinic in Denmark. All new patients were included and evaluations were conducted after six and 12 months. Pharmacological and non-pharmacological treatments were offered by a team of specialists (physicians, headache nurses, a physiotherapist and a psychologist). The subjects comprised 169 children (mean age 11.7 (range 4-17), 91 females, 78 males), 39% of whom suffered from chronic headache (≥15 days/month). All children were diagnosed according to the International Classification of Headache Disorders, second edition; 20% had migraine, 34% tension-type headache, 27% mixed headache, 4% medication-overuse headache, and 15% were diagnosed with other types of headaches. Fifty per cent of the children had an improvement in headache frequency above 50% at six months. By the use of repeated measurement analysis, we found a significant decrease in headache frequency in all of the six headache groups, whereas the increase in quality of life (PedsQL™ 4.0) was significant for the group as a whole. Though preliminary, the results show a good outcome for multidisciplinary treatment programmes for children who suffer from frequent or chronic headache.


Do people with disabilities have difficulty finding a family physician?
Primary care has been ideally characterized as the medical home for all citizens, and yet recent data shows that approximately 6% do not have a family physician, and only 17.5% of family practices are open to new patients. Given acknowledged shortages of family physicians, this research asks the question: Do people with disabilities have particular difficulty finding a family physician? Health Care Connect (HCC) is a government-funded agency in Ontario Canada, designed to "help Ontarians who are without a family health care provider to find one". Using data from HCC, supplemented by interviews with HCC staff, the study explores the average wait time for patients with disabilities to be linked with a primary care physician, and the challenges faced by agency staff in doing so. The study found that disabled registrants with the program are only slightly disadvantaged in terms of wait times to find a family physician, and success rates are ultimately comparable; however, agency staff report that there are a number of significant challenges associated with placing disabled patients.


Somatosensory evoked response and jaw opening reflex elicited by tooth pulp stimulation in awake freely moving rats.
Investigation of pain and nociception refers to different models. Depending upon the intensity of stimulation, unmyelinated pulpal fibers or periodontal A-fibers can be stimulated producing a short or a long latency jaw opening reflex of the digastric muscle. This paper investigates the different components of the jaw opening reflex in addition to the correlation between afferent fibers involved in the cortical evoked response. Fifteen awake male rats were implanted with tooth pulp stimulation electrodes, digastric and cortical recording electrodes. Ten rats were submitted to recordings after a single tooth pulp stimulation, while five rats were using conditioning and test stimulation. Tooth pulp evoked potentials and digastric EMG were simultaneously recorded. A multiresolution denoising method was used for signal processing. Following tooth pulp stimulation, a cortical response was produced including the following peaks: P6.5 +/- 1.1, N11 +/- 1.2, P17 +/- 1.2, P27 +/- 2.9, N53 +/- 7.5, P69 +/- 5.8, P88 +/- 13, N160 +/- 9.7, P204 +/- 14.2. The distribution and amplitude of these peaks are correlated to the stimulation intensity (r=0.96, p<0.01). An interaction between the different components of the jaw opening reflex was identified on EMG, following a conditioning shock, where a cortical evoked response showed a P30 +/- 2.7 peak which was observed concurrently with the jaw opening long latency reflex. Our results identify the interaction between the different components of the jaw opening reflex and the correlation to the cortical evoked response.


Initial efficacy of a cardiac rehabilitation transition program: Cardiac TRUST.
The purpose of this pilot study was to test the initial efficacy, feasibility, and safety of a specially designed postacute care transitional rehabilitation intervention for cardiac patients. Cardiac Transitional Rehabilitation Using Self-Management Techniques (Cardiac TRUST) is a family-focused intervention that includes progressive low-intensity walking and education in self-management skills to facilitate recovery following a cardiac event. Using a randomized two-group design, exercise self-efficacy, steps walked, and participation in an outpatient cardiac rehabilitation (CR) program were compared in a sample of 38 older adults (17 Cardiac TRUST, 21 usual care). At discharge from postacute care, the intervention group trended toward higher levels of self-efficacy for exercise outcomes than the usual care group. During the 6 weeks following discharge, the intervention group had greater attendance in outpatient CR and a trend toward more steps walked during the first week. The feasibility of the intervention was better for the home health care participants than for those in the skilled nursing facility. The provision of CR during postacute care has the potential to bridge the gap in transitional services from hospitalization to outpatient CR for these patients at high risk for future cardiac events. Further evidence of the efficacy of Cardiac TRUST is warranted.


Stray-field imaging of magnetic vortices with a single diamond spin.
Despite decades of advances in magnetic imaging, obtaining direct, quantitative information with nanometre scale spatial resolution remains an outstanding challenge. Recently, a technique has emerged that employs a single nitrogen-vacancy defect in diamond as an atomic-size magnetometer, which promises significant advances. However, the effectiveness of the technique when applied to magnetic nanostructures remains to be demonstrated. Here we use a scanning nitrogen-vacancy magnetometer to image a magnetic vortex, which is one of the most iconic objects of nanomagnetism, owing to the small size (~10 nm) of the vortex core. We report three-dimensional, vectorial and quantitative measurements of the stray magnetic field emitted by a vortex in a ferromagnetic square dot, including the detection of the vortex core. We find excellent agreement with micromagnetic simulations, both for regular vortex structures and for higher-order magnetization states. These experiments establish scanning nitrogen-vacancy magnetometry as a practical and unique tool for fundamental studies in nanomagnetism.


Role for Protein Kinase A in the Neurospora Circadian Clock by Regulating White Collar-Independent frequency Transcription through Phosphorylation of RCM-1.
Rhythmic activation and repression of clock gene expression is essential for the eukaryotic circadian clock functions. In the Neurospora circadian oscillator, the transcription of the frequency (frq) gene is periodically activated by the White Collar (WC) complex and suppressed by the FRQ-FRH complex. We previously showed that there is WC-independent frq transcription and its repression is required for circadian gene expression. How WC-independent frq transcription is regulated is not known. We show here that elevated protein kinase A (PKA) activity results in WC-independent frq transcription and the loss of clock function. We identified RCM-1 as the protein partner of RCO-1 and an essential component of the clock through its role in suppressing WC-independent frq transcription. RCM-1 is a phosphoprotein and is a substrate of PKA in vivo and in vitro. Mutation of the PKA-dependent phosphorylation sites on RCM-1 results in WC-independent transcription of frq and impaired clock function. Furthermore, we showed that RCM-1 is associated with the chromatin at the frq locus, a process that is inhibited by PKA. Together, our results demonstrate that PKA regulates frq transcription by inhibiting RCM-1 activity through RCM-1 phosphorylation.


How to teach medication management: a review of novel educational materials in geriatrics.
Medication management is an important component of medical education, particularly in the field of geriatrics. The Association of American Medical Colleges has put forth 26 minimum geriatrics competencies under eight domains for graduating medical students; medication management is one of these domains. The Portal of Geriatric Online education (www.POGOe.org) is an online public repository of geriatrics educational materials and modules developed by geriatrics educators and academicians in the United States, freely available for use by educators and learners in the field. The three POGOe materials presented in this review showcase pearls of medication management for medical and other professional students in novel learning formats that can be administered without major prior preparation. The review compares and contrasts the three materials in descriptive and tabular formats to enable its appropriate use by educators in promoting self-learning or group learning among their learners.


Prescription habits of dispensing and non-dispensing doctors in Zimbabwe.
The number of dispensing doctors has increased in the last decade, but the implication of this trend on the quality of health care and drug use is unknown. We present a comparative drug utilization study of 29 dispensing doctors and 28 non-dispensing doctors in Zimbabwe based on standard indicators developed by the World Health Organization. Dispensing doctors prescribed significantly more drugs per patient than non-dispensing doctors (2.3 versus 1.7), injected more patients (28.4% versus 9.5%), and prescribed more antibiotics (0.72 versus 0.54) and mixtures (0.43 versus 0.25) per encounter. Dispensing doctors also spent significantly less time on each encounter (8.7 min versus 13.0 min) than their non-dispensing colleagues. The use of generic name, brand name and essential drugs did not differ significantly between the two groups of practitioners. Multivariate analyses controlling for gender, race, place of education, location of practice and patients seen per day showed that dispensing by doctors was associated with less clinically and economically appropriate prescribing. These findings suggest that the quality of health care--as related to drug use, patient safety and treatment cost--is lower with dispensing doctors than with non-dispensing doctors.


A qualitative study of smoking behavior among the floating population in Shanghai, China.
China has become the world's largest producer and consumer of tobacco and lung cancer is China's leading cause of cancer deaths. The large majority of Chinese smokers are men. Tobacco consumption is of particular concern among China's internal floating (or migrant) population, which has become a permanent feature of Chinese society, because this population is very large (over 100 million persons) and it has a high prevalence of smoking. Considering additionally that like the general population of China, the smoking prevalence rate of women from this group is quite low, we therefore aimed to explore smoking-related knowledge, attitudes and behaviours among male smokers in the floating population to help inform the development of effective smoking cessation interventions in this important target group in China. We interviewed 39 floating population male smokers in six focus groups and performed a qualitative content analysis of the interviews. Most participants knew that smoking is risky to health but they knew little about why. Habit and social participation were key drivers of smoking. Smoking was regarded as a core component of their identity by the urban residents. Some participants had tried to stop smoking but none reported having ever been educated about smoking. Smoking cessation interventions for China's male floating population would need to incorporate comprehensive education and information about why smoking is dangerous and the benefits of stopping.


Pediatric epilepsies misdiagnosed as gastrointestinal disorders.
In the last years, several cases of pediatric epilepsies misdiagnosed and treated as gastrointestinal (GI) disorders have been reported. The aim of this study was to evaluate both frequency and characteristics of these erroneous diagnoses. We identified children who had received a previous misdiagnosis of GI disorder out of 858 consecutive patients with a diagnosis of epilepsy at our hospital from 2010 to 2015. Misdiagnosis was observed in 21 patients (2.4%): 7 children with West syndrome, 10 with temporal lobe epilepsy, and 4 with Panayiotopoulos syndrome. The majority of children with a misdiagnosis (12/21) were younger than 1year at epilepsy onset, and median diagnostic delay was 15.5months. The most frequently diagnosed GI disorder was gastroesophageal reflux disease, especially in younger children. The study confirms that epilepsy in a significant percentage of children is wrongly identified and treated as GI disorders. In particular, epilepsy should be considered in the differential diagnosis of "atypical" gastroesophageal reflux in younger children in order to avoid serious prognostic consequences.


Determining appropriate screening tools and cut-points for cognitive impairment in an elderly Chinese sample.
The establishment of normative data and screening cut-points for cognitive tasks is important to ensure the effective and timely detection of mild cognitive impairment (MCI) and Alzheimer's disease (AD). These need to be culturally relevant and account for known factors that impact on cognition such as age, education, and gender. In this study, 1,068 elderly Chinese residents of Shanghai completed a comprehensive series of cognitive tasks as part of a community screening study with 1027 meeting criteria for analysis, age M(SD) = 72.54 (8.40). MCI was detected in 267 individuals, AD in 50, and 710 had normal cognition. Receiver Operator Characteristic curve analysis indicated that the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) best differentiated normal cognition from MCI and AD. We present suggested cut-points to differentiate between normal cognition and MCI and AD for the total sample, and when split according to education levels, age, and gender. Trends suggest that the MoCA was better suited to detecting MCI, and the MMSE was better for detecting AD. For younger and more educated participants, only a slight impairment was necessary to meet screening criteria, while a larger impairment was necessary for older and less educated participants. Both tasks had a high negative predictive values for MCI and AD, and variable positive predictive values. The cut-points presented can be used to inform future work using the MMSE and MoCA to screen for MCI and AD in older Chinese people. (PsycINFO Database Record


The amino terminus of the Saccharomyces cerevisiae DNA helicase Rrm3p modulates protein function altering replication and checkpoint activity.
The Pif1 family of DNA helicases is conserved from yeast to humans. Although the helicase domains of family members are well conserved, the amino termini of these proteins are not. The Saccharomyces cerevisiae genome encodes two Pif1 family members, Rrm3p and Pif1p, that have very different functions. To determine if the amino terminus of Rrm3p contributes to its role in promoting fork progression at >1000 discrete chromosomal sites, we constructed a deletion series that lacked portions of the 249-amino-acid amino terminus. The phenotypes of cells expressing alleles that lacked all or most of the amino terminus were indistinguishable from those of rrm3Delta cells. Rrm3p deletion derivatives that lacked smaller portions of the amino terminus were also defective, but the extent of replication pausing at tRNA genes, telomeres, and ribosomal DNA (rDNA) was not as great as in rrm3Delta cells. Deleting only 62 amino acids from the middle of the amino terminus affected only rDNA replication, suggesting that the amino terminus can confer locus-specific effects. Cells expressing a fusion protein consisting of the Rrm3p amino terminus and the Pif1p helicase domain displayed defects similar to rrm3Delta cells. These data demonstrate that the amino terminus of Rrm3p is essential for Rrm3p function. However, the helicase domain of Rrm3p also contributes to its functional specificity.


Corporal reactivity to adenosine and prostaglandin E1 in alloxan-induced diabetic rabbit corpus cavernosum, and the effect of insulin therapy.
To investigate the changes in corporal reactivity to adenosine and prostaglandin E1 (PGE1 ) in corpus cavernosal strips from alloxan-induced diabetic rabbits and to determine the effects of insulin therapy. Twenty-four New Zealand white rabbits were studied in three equal groups: group 1, control; group 2, diabetes induced by the administration of alloxan hydrochloride intravenously; group 3, as group 2 but with insulin administered after the induction of diabetes. At the end of 8 weeks, the reactivity of corpus cavernosal strips from the animals was assessed in organ chambers. The relaxation responses of corpus cavernosal strips to adenosine were similar in all groups, but the response to PGE1 was impaired in groups 2 and 3 compared with that in controls. If vasoactive drugs are to be used for the diagnosis or treatment of diabetic erectile impotence, direct-acting vasodilators, e.g. adenosine, must be used. In alloxan-induced diabetes, the corporal reactivity to PGE1 was impaired and insulin therapy did not restore the relaxation responses.


Electronic fetal monitoring in the United States in the 1980s.
To measure the frequency with which electronic fetal monitoring was used for childbirth in United States hospitals in the 1980s and to examine variation in use according to risk factors at labor onset. Two data sets from the National Center for Health Statistics (the 1980 National Natality Survey and the 1988 National Maternal and Infant Health Survey) were used to generate proportional frequencies for electronic fetal monitoring use. These data files are based on representative samples of live births (9941 and 9953, respectively) drawn by probability methods from the entire country during a calendar year. Consistency in the sampling methods and questionnaire procedures, and use of sampling weights, permitted national estimates to be generated. Use of electronic fetal monitoring increased from 44.6% of live births in 1980 to 62.2% in 1988. In both time periods, low-risk women received monitoring more frequently than did women with risk indicators. Use grew by 64% in low-risk women (from 46.5% in 1980 to 76.3% in 1988) but only by 32% in women with risk conditions at labor onset (from 42.6% in 1980 to 56.2% in 1988). Use of electronic fetal monitoring increased during the 1980s, disproportionately so for low-risk women. This trend raises questions about the efficacy of monitoring for improving pregnancy outcomes.


The influence of substance use on adolescent brain development.
Adolescence is a unique period in neurodevelopment. Alcohol and marijuana use are common. Recent research has indicated that adolescent substance users show abnormalities on measures of brain functioning, which is linked to changes in neurocognition over time. Abnormalities have been seen in brain structure volume, white matter quality, and activation to cognitive tasks, even in youth with as little as 1-2 years of heavy drinking and consumption levels of 20 drinks per month, especially if > 4-5 drinks are consumed on a single occasion. Heavy marijuana users show some subtle anomalies too, but generally not the same degree of divergence from demographically similar non-using adolescents. This article reviews the extant literature on neurocognition, brain structure, and brain function in adolescent substance users with an emphasis on the most commonly used substances, and in the context of ongoing neuromaturational processes. Methodological and treatment implications are provided.


The impact of Type 2 diabetes prevention programmes based on risk-identification and lifestyle intervention intensity strategies: a cost-effectiveness analysis.
To develop a cost-effectiveness model to compare Type 2 diabetes prevention programmes targeting different at-risk population subgroups with a lifestyle intervention of varying intensity. An individual patient simulation model was constructed to simulate the development of diabetes in a representative sample of adults without diabetes from the UK population. The model incorporates trajectories for HbA1c , 2-h glucose, fasting plasma glucose, BMI, systolic blood pressure, total cholesterol and HDL cholesterol. Patients can be diagnosed with diabetes, cardiovascular disease, microvascular complications of diabetes, cancer, osteoarthritis and depression, or can die. The model collects costs and utilities over a lifetime horizon. The perspective is the UK National Health Service and personal social services. We used the model to evaluate the population-wide impact of targeting a lifestyle intervention of varying intensity to six population subgroups defined as high risk for diabetes. The intervention produces 0.0003 to 0.0009 incremental quality-adjusted life years and saves up to £1.04 per person in the general population, depending upon the subgroup targeted. Cost-effectiveness increases with intervention intensity. The most cost-effective options are to target individuals with HbA1c > 42 mmol/mol (6%) or with a high Finnish Diabetes Risk (FINDRISC) probability score (> 0.1). The model indicates that diabetes prevention interventions are likely to be cost-effective and may be cost-saving over a lifetime. In the model, the criteria for selecting at-risk individuals differentially impact upon diabetes and cardiovascular disease outcomes, and on the timing of benefits. These findings have implications for deciding who should be targeted for diabetes prevention interventions.


The Noninvasive Assessment of Vascular Aging.
The growing interest in the clinical measurement of arterial aging through the noninvasive assessment of arterial stiffness is associated with important developments in novel methods and apparatus. In this review, we aimed to describe the major principles of the measurement of arterial stiffness and to critically review the advantages and limitations of the different methods. The measurement of regional stiffness is recommended by international guidelines for routine clinical practice. It is most often determined through pulse wave velocity (PWV) between 2 arterial sites. Methods using a single-site cuff-based measurement are promising. Local determination of arterial stiffness, obtained either with the well-established, high-resolution echo tracking systems or more recently with magnetic resonance imaging, is indicated for pathophysiological and pharmacologic studies. Novel apparatus that were developed for determining arterial stiffness claimed superiority over pioneering methods either through greater simplicity of use, better repeatability, or a more pertinent arterial pathway. However, the true additive value of measuring arterial aging with a given apparatus had to be translated into the predictive value of arterial stiffness as an intermediate end point, ie, the higher the arterial stiffness the higher the number of cardiovascular (CV) events. Thus, another important aim of this review was to analyze the amount of epidemiologic evidence obtained with a given method regarding the predictive value of arterial stiffness for CV events.


One-handed chest compression technique for paediatric cardiopulmonary resuscitation: dominant versus non-dominant hand.
Pediatric resuscitation guidelines do not specify which hand to use for one-handed cardiopulmonary resuscitation (CPR). To determine whether there is a difference in the quality of one-handed chest compressions (OHCCs) using the dominant versus non-dominant hand in simulated paediatric CPR. 41 doctors took part in the study. Chest compressions were alternately performed with the dominant (test 1) and non-dominant hand (test 2) in a random order at 30 min intervals. Experiments were carried out with a 5-year-old paediatric manikin without ventilation for 2 min. Data on average compression rate (per min) and average compression depth (mm) were collected and compared. No significant differences were found in the average compression rate (118.0±14.3/min vs 117.3±14.5/min, p=0.610) and average compression depth (41.3±5.6mm vs 41.9±4.1mm, p=0.327) between tests 1 and 2. No significant difference was found in the quality of OHCCs using the dominant and non-dominant hand in simulated paediatric CPR. The study suggests there is no need for paediatric resuscitation guidelines to state a preferred hand for performing OHCC.


Antiviral effect of methylated flavonol isorhamnetin against influenza.
Influenza is an infectious respiratory disease with frequent seasonal epidemics that causes a high rate of mortality and morbidity in humans, poultry, and animals. Influenza is a serious economic concern due to the costly countermeasures it necessitates. In this study, we compared the antiviral activities of several flavonols and other flavonoids with similar, but distinct, hydroxyl or methyl substitution patterns at the 3, 3', and 4' positions of the 15-carbon flavonoid skeleton, and found that the strongest antiviral effect was induced by isorhamnetin. Similar to quercetin and kaempferol, isorhamnetin possesses a hydroxyl group on the C ring, but it has a 3'-methyl group on the B ring that is absent in quercetin and kaempferol. Co-treatment and pre-treatment with isorhamnetin produced a strong antiviral effect against the influenza virus A/PR/08/34(H1N1). However, isorhamnetin showed the most potent antiviral potency when administered after viral exposure (post-treatment method) in vitro. Isorhamnetin treatment reduced virus-induced ROS generation and blocked cytoplasmic lysosome acidification and the lipidation of microtubule associated protein1 light chain 3-B (LC3B). Oral administration of isorhamnetin in mice infected with the influenza A virus significantly decreased lung virus titer by 2 folds, increased the survival rate which ranged from 70-80%, and decreased body weight loss by 25%. In addition, isorhamnetin decreased the virus titer in ovo using embryonated chicken eggs. The structure-activity relationship (SAR) of isorhamnetin could explain its strong anti-influenza virus potency; the methyl group located on the B ring of isorhamnetin may contribute to its strong antiviral potency against influenza virus in comparison with other flavonoids.


Connectivity-based segmentation of the substantia nigra in human and its implications in Parkinson's disease.
The aims of this study were to i) identify substantia nigra subregions i.e. pars reticulata (SNr) and pars compacta (SNc), in human, and ii) to assess volumetric changes in these subregions in the diagnosis of Parkinson's disease. Current MR imaging techniques are unable to distinguish SNr and SNc. Segmentation of these regions may be clinically useful in Parkinson's disease (PD) as substantia nigra is invariably affected in PD. We acquired quantitative T1 as well as diffusion tensor imaging (DTI) data from ten healthy subjects and ten PD patients. For each subject, the left and right SN were manually outlined on T1 images and then classified into two discrete regions based on the characteristics of their connectivity with the rest of the brain using an automated clustering method on the DTI data. We identified two regions in each subjects' SN: an internal region that is likely to correspond with SNc because it was mainly connected with posterior striatum, pallidum, anterior thalamus, and prefrontal cortex; and an external region that corresponds with SNr because it was chiefly connected with posterior thalamus, ventral thalamus, and motor cortex. Volumetric study of these regions in PD patients showed a general atrophy in PD particularly in the right SNr. This pilot study showed that automated DTI-based parcellation of SN subregions may provide a useful tool for in-vivo identification of SNc and SNr and might therefore assist to detect changes that occur in patients with PD.


Characteristics of self-inflicted injury among suicidal patients: analysis of nation-wide trauma registry.
Self-inflicted injury is one of the most common causes of suicide. Extremity injury is thought to occur most frequently among penetrating injury; however, epidemiology among patients attempting suicide is unknown. This study aims to find the characteristics of penetrating self-inflicted trauma patients. This is a retrospective cohort study of Japanese nation-wide trauma registry (the Japan National Trauma Data Bank) between January 1, 2004 and December 31, 2017. Patients who attempted suicide with penetrating injury were eligible. We evaluated the occurrence of injury based on injury site (neck/face, chest, abdomen, extremity) as a dependent variable and aging as an independent variable using a generalized linear model and compare those groups with spline models. 4576 trauma patients were eligible. Excluding patients with missing age, missing survival data, and missing abbreviate injury score, 4183 patients were enrolled in this study. Common injury site is follows: abdomen 1772 patients (42.4%), extremity 1344 patients (32.0%), neck/face 1253 patients (30.0%), and chest 993 patients (23.7%). The occurrence of neck/face injury, chest injury, and abdominal injury increased with age. On contrary, the rate of extremity injury decreased with age. Among self-inflicted trauma patients, abdominal injury was the most common injury, and neck/face injury, chest injury, and abdominal injury were related with aging. On the contrary, the rate of extremity injury decreased as patients' age progressed. Retrospective cohort study, Level III.


Negative and positive childhood experiences across developmental periods in psychiatric patients with different diagnoses - an explorative study.
A high frequency of childhood abuse has often been reported in adult psychiatric patients. The present survey explores the relationship between psychiatric diagnoses and positive and negative life events during childhood and adulthood in psychiatric samples. A total of 192 patients with diagnoses of alcohol-related disorders (n = 45), schizophrenic disorders (n = 52), affective disorders (n = 54), and personality disorders (n = 41) completed a 42-item self-rating scale (Traumatic Antecedents Questionnaire, TAQ). The TAQ assesses personal positive experiences (competence and safety) and negative experiences (neglect, separation, secrets, emotional, physical and sexual abuse, trauma witnessing, other traumas, and alcohol and drugs abuse) during four developmental periods, beginning from early childhood to adulthood. Patients were recruited from four Psychiatric hospitals in Germany, Switzerland, and Romania; 63 subjects without any history of mental illness served as controls. The amount of positive experiences did not differ significantly among groups, except for safety scores that were lower in patients with personality disorders as compared to the other groups. On the other side, negative experiences appeared more frequently in patients than in controls. Emotional neglect and abuse were reported in patients more frequently than physical and sexual abuse, with negative experiences encountered more often in late childhood and adolescence than in early childhood. The patients with alcohol-related and personality disorders reported more negative events than the ones with schizophrenic and affective disorders. The present findings add evidence to the relationship between retrospectively reported childhood experiences and psychiatric diagnoses, and emphasize the fact that a) emotional neglect and abuse are the most prominent negative experiences, b) adolescence is a more 'sensitive' period for negative experiences as compared to early childhood, and c) a high amount of reported emotional and physical abuse occurs in patients with alcohol-related and personality disorders respectively.


Effect of Ginger and Novafen on menstrual pain: A cross-over trial.
Menstrual pain is a periodic pain which happens during the days of menses. The menstrual disturbances as a health problem among young girls affect not only reproductive, but also psychical health and quality of life. This study was done with the goal of comparing the effect of Ginger and Novafen on the menstrual pain. This crossover clinical trial study was done in Iran on 168 single girl students 18-26 years old in Babol University of Medical Sciences with primary menstrual pain. The participants were randomly allocated to two groups receiving the drugs Novafen and Ginger. At the beginning of pain, in the two groups 200 mg capsule was given every 6 h for two serial cycles. Pain severity was measured by the visual scale before treatment, 1 h after consuming the drug (for 24 h) and 48 h after the onset of drug. The mean age of participants was 21.83 ± 2.07 years. It has been reported that the intensity of pain from dysmenorrhea decreased in the Novafen and Ginger groups. Before treatment, the average pain intensity in Novafen and Ginger users were 7.12 ± 2.32 and 7.60 ± 1.84, respectively and after treatment pain intensity decreased to 3.10 ± 2.69 and 2.97 ± 2.69, respectively. Differences between two groups each time showed no statistical significance (p > 0.05). Both drugs reduced menstrual pain. Ginger as well as Novafen is effective in relieving pain in girls with primary dysmenorrhea . Therefore, treatment with natural herbal medicine, non-synthetic drug, to reduce primary dysmenorrhea is recommended.


Determinants of physical activity: A path model based on an ecological model of active living.
Maintaining physical activity is necessary to promote health in our daily lives. The Ecological Model of Active Living was proposed to examine whether individuals participate in active living. The purpose of this study was to understand the determinants of physical activity and create a predictive path model of the intrapersonal, perceived environment, behavior settings, and policy environment domains. Data were obtained from open government data and questionnaires, including the International Physical Activity Questionnaire, Health Belief Model Inventory, Physical Activity Neighborhood Environment Survey, and Accessibility of Open Spaces. Participants comprised 1085 healthy adults who completed a self-reported internet survey. An analysis of the intrapersonal domain revealed that the variables of female, an older age, and a low educational level, and individuals with obesity or cardiometabolic diseases presented lower odds ratios for active living. We found significant statistical support for our path model (The Ecological Model of Active Living), with a predictive power of 23.1%. The predictive path model is a good approach to quantitatively measure the impacts of various determinants on active living that suggests further lines of research in approaches for modeling relationships.


Are older cancer patients being referred to oncologists? A mail questionnaire of Ontario primary care practitioners to evaluate their referral patterns.
Understanding why older patients are frequently underrepresented in cancer services use and clinical research may help to increase their participation in clinical trials and eventually result in better cancer care for this vulnerable population. To identify potential barriers that may prevent older cancer patients from being referred from a primary care physician (PCP) to an oncology specialist, a self-administered questionnaire was mailed to 9,312 PCPs throughout Ontario. With a one-time mailing, 2,240 questionnaires were returned (response rate, 24%) of which 2,089 (93%) were assessable. Although 86% of respondents would refer most older patients with early-stage, potentially curable cancers to oncologists, only 65% would refer those with advanced-stage, potentially incurable cancers. The factors that most influence referral decisions of PCPs are patient's desire to be referred (69%), type (54%) and stage (49%) of cancer, and severity of cancer symptoms (49%). Other factors including age do not seem to influence the referral decision. Approximately 9% of respondents found it difficult to refer older cancer patients to oncology specialists, with the most commonly cited barriers being the length of waiting lists, mandatory tissue diagnosis before referral, and the belief that oncologists seldom relate to PCPs. Most PCPs stated that they would refer all elderly patients with cancer to oncologists and that referral decisions were based mainly on patients' wishes. Continued efforts are needed to overcome barriers in the referral process and to understand the perspectives of elderly patients to enhance their cancer care.


Green fluorescent chimeras indicate nonpolar localization of pullulanase secreton components PulL and PulM.
The Klebsiella oxytoca pullulanase secreton (type II secretion system) components PulM and PulL were tagged at their N termini with green fluorescent protein (GFP), and their subcellular location was examined by fluorescence microscopy and fractionation. When produced at moderate levels without other secreton components in Escherichia coli, both chimeras were envelope associated, as are the native proteins. Fluorescent GFP-PulM was evenly distributed over the cell envelope, with occasional brighter foci. Under the same conditions, GFP-PulL was barely detectable in the envelope by fluorescence microscopy. When produced together with all other secreton components, GFP-PulL exhibited circumferential fluorescence, with numerous brighter patches. The envelope-associated fluorescence of GFP-PulL was almost completely abolished when native PulL was also produced, suggesting that the chimera cannot compete with PulL for association with other secreton components. The patches of GFP-PulL might represent functional secretons, since GFP-PulM also appeared in similar patches. GFP-PulM and GFP-PulL both appeared in spherical polar foci when made at high levels. In K. oxytoca, GFP-PulM was evenly distributed over the cell envelope, with few patches, whereas GFP-PulL showed only weak envelope-associated fluorescence. These data suggest that, in contrast to their Vibrio cholerae Eps secreton counterparts (M. Scott, Z. Dossani, and M. Sandkvist, Proc. Natl. Acad. Sci. USA 98:13978-13983, 2001), PulM and PulL do not localize specifically to the cell poles and that the Pul secreton is distributed over the cell surface.